Recent U.S. Mental Health Surveys report alarmingly high lifetime prevalence rates of 20.8% and 28.8% for mood disorders and anxiety disorders, respectively (R. C. Kessler et al. Lifetime Prevalence And Age-Of-Onset Distributions Of DSM-IV Disorders In The National Comorbidity Survey Replication, 62 Arch. Gen. Psychiatry 593-02 (2005)). While most who suffer from these clinical syndromes indeed seek treatment help, antidepressant therapies that target monoaminergic (MA) systems are problematic as they require 4-6 weeks of administration to achieve effects, are accompanied by unpleasant side effects, possess modest efficacy rates (65%), and display significant relapse rates (M. E. Thase. Handbook of Depression, I. H. Gotlib & C. L. HAMMEN (eds.) pp. 187-216 (Guilford Press, New York, 2008)). Compounding this problem, for depression, is that no real new drug class has entered clinical use in the last 40 years (E. J. Nestler. Antidepressant Treatments in the 21st Century, 44 Biol. Psych. 526-33 (1998)). However, recent studies have indicated that low-doses of the N-Methyl-D-aspartate (NMDA) receptor antagonist ketamine produce rapid antidepressant effects in treatment-resistant depression (R. M. Berman et al. Antidepressant effects of ketamine in depressed patients, 47 Biol. Psychiatry 351-4 (2000); C. A. Zarate et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression, 63 Arch. Gen. Psychiatry 856-64 (2006)), defined as being insensitive to two classes of FDA-approved antidepressants and depression with suicidal ideation (R. B. Price et al. Effects of Intravenous Ketamine on Explicit and Implicit Measures of Suicidality in Treatment-Resistant Depression, 66 Biol. Psychiatry 522-(2009)). Increases in success rates for the treatment of these and other syndromes rely, in part, on the discovery of novel pharmacotherapeutics in clinically relevant animal models and screening assays.
Rodent-based models have long been the mainstay in behavioral pharmacology research and there exist a number of screening assays to detect anxiolytic or antidepressant activity of novel drug candidates. However, rodent models can be labor-intensive and time consuming, are typically expensive to conduct, fail to model the diverse clinical features of depression including co-morbidity with anxiety disorders, and may demonstrate weak treatment or drug effects, or worse, suffer from false positives and false negatives.
Research from this laboratory has developed an in vivo high utility, high-throughput model for screening anxiolytic drugs in domestic fowl chicks (K. J. Sufka et al. Construct Validation of Behavioral Indices of Isolation Stress and Inflammatory Nociception in Young Domestic Fowl, 55 Physiol. Behav. 741-46 (1994); G. S. Watson et al. Chlordiazepoxide Reverses Social-Separation-Induced Distress Vocalizations and Analgesia in Young Domestic Fowl, 4 Exp. Clin. Psychopharm. 347-53 (1996)). Using separation-induced distress vocalizations (DVocs) to index anxiety (G. S. Watson et al. 1996, supra), my laboratory has developed a set of procedures that allows for preclinical anxiolytic drug efficacy screening. (M. W. Feltenstein et al. The Chick Separation Stress Paradigm: A Validation Study, 77 Pharmacol. Biochem. Behav. 221-26 (2004); M. W. Feltenstein et al. Anxiolytic Properties of Piper Methysticum Extract Samples and Fractions in the Chick Social-Separation-Stress Procedure, 17 Phytother. Res. 210-16 (2003)). The chick separation stress paradigm possesses construct validity as an anxiety model in that separation stress reliably increases corticosterone levels (M. W. Feltenstein et al. Dissociation of Stress Behaviors in the Chick Social-Separation-Stress Procedure, 75 Physiol. Behav. 675-79 (2002)), a neuroendocrine marker of many stress responses. The model possesses predictive validity through the successful detection of diverse classes of anxiolytics (i.e., meprobamate, pentobarbital, chlordiazepoxide, imipramine and clonidine; (M. W. Feltenstein et al. 2004, supra), and is sensitive to potency differences within an anxiolytic class (i.e., alprazolam, lorazepam and chlordiazepoxide; (G. S. Watson et al. Benzodiazepine Receptor Function in the Chick Social-Separation-Stress Procedure, 7 Exp. Clin. Psychopharm. 83-89 (1999)). Furthermore, the model is insensitive to a wide range of nonanxiolytic compounds (i.e., amphetamine, scopolamine, caffeine, chlorpromazine, and haloperidol; (M. W. Feltenstein et al. 2004, supra). Finally, this paradigm has been used to identify anxiolytic activity in botanical extracts, extract fractions and isolated constituents in products marketed to consumer (K. J. Sufka et al. Anxiolytic Properties Of Botanical Extracts In The Chick Social Separation-Stress Procedure, 153 Psychopharm. 219-24 (2004)).
Domestic fowl chicks have also been used to model depression. (E. Lehr. Distress Call Reactivation in Isolated Chicks: Behavioral Indicator With High Selectivity for Antidepressant Drugs, 97 Psychopharm. 145-46 (1989)) reports that chicks isolated for two hours entered into what was described as a “learned helplessness” state, a behavioral profile commonly associated with depression. In this study, Lehr reports that a wide variety of putative antidepressant drugs reversed this learned helplessness state while those lacking antidepressant activity did not. Unfortunately, a fine-grained analysis of this work is all but impossible as very limited methodological details (e.g., use of total count of distress vocalizations for the two hour period) and resultant data (e.g., all data presented as drug dose values in mg/kg for either 150% or 50% effect of control) were published. Nevertheless, what can be ascertained from this two-page report is that this paradigm, I believe, most certainly conflates two or more clinical syndromes.
One current perspective among some clinical psychologists suggests that anxiety and major depression may represent a single syndrome that only differs in symptom severity and/or duration. This notion is based on significant overlap in signs and symptoms of the two disorders and co-morbidity rates of approximately 70% between anxiety and depression (R. C. Kessler et al. Lifetime And 12-Month Prevalence Of DSM-III-R Psychiatric Disorders In The United States: Results For The National Comorbidity Survey, 51 Archives of General Psychiatry, 355-64 (1994)). However, no one has developed a pre-clinical drug-screening model that accurately displays homologies to the clinical features in depressive disorders of the co-morbidity of anxiety and depression in treatment-resistant subjects, which may account for a third or more of the clinical patient population.